Submission Details

The IMPG1 gene was first reported in relation to ocular disease in 2004, in affected members of a family with an autosomal dominant pattern of inheritance (PMID: 14691150). The known spectrum of disease expanded to include cases with autosomal recessive inheritance with the 2013 identification of IMPG1 variants in association with vitelliform macular dystrophy (PMID: 23993198). IMPG1 variants have also been identified as the basis for cases of retinitis pigmentosa with both autosomal dominant (PMID: 32817297) and autosomal recessive (PMID: 32817297) modes of inheritance, indicating the potential for a broad range of phenotypic presentations. Autosomal recessive cases diagnosed with retinitis pigmentosa 91 generally exhibit features such as night blindness, bone spicule pigmentation of the retina, drusen, a ring of hyper-autofluorescence, retinal thinning / fundus atrophy, retinal blood vessel attenuation, and/or optic disc pallor. Reported cases diagnosed as vitelliform macular dystrophy 4 generally exhibit features such as vitelliform-like macular lesions, foveal detachment, small yellow foveal spots, and/or choroidal neovascularization. Some of the retinitis pigmentosa and vitelliform macular dystrophy cases are reported with reduced visual acuity and reduced electroretinogram (particularly dark-adapted) responses. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (biallelic IMPG1 loss of function) was found to be consistent among patients with recessive inheritance of vitelliform macular dystrophy (MIM# 616151) or retinitis pigmentosa (MIM# 153870), The phenotypic variability between them appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic IMPG1 variants have been lumped into a single disease entity, referred to as IMPG1-related recessive retinopathy. On the other hand, carriers from families with autosomal recessive disease have only been subclinically affected, prompting the group to recommend splitting the autosomal dominant cases into a separate curation for IMPG1-related dominant retinopathy.

Eight suspected disease-causing variants were scored as part of this curation (one nonsense, four affecting splicing, and three missense), which have been collectively reported in seven probands in four publications (PMID: 23993198, PMID: 28644393, PMID: 32817297, PMID: 32531858). All of the probands scored in this curation harbored biallelic IMPG1 variants. The mechanism of pathogenicity appears to be biallelic loss of IMPG1 function conferred by null and/or hypomorphic variants. Interestingly, biallelic variants appear to be associated with complete penetrance, while monoallelic variants are generally incompletely penetrant. Large families with a recessive mode of inheritance were not found in the literature, and segregation evidence did not contribute to the scoring of this curation.

This gene-disease association is also supported by biochemical evidence that IMPG1 encodes a component of the interphotoreceptor matrix (PMID: 10601738), an insoluble extracellular layer located between the retinal pigment epithelium and the neural retina that is known to support the function and maintenance of photoreceptor cells (PMID: 7344830). The IMPG2 gene similarly encodes a component of this structure and harbors variants associated with vitelliform macular dystrophy 5 and retinitis pigmentosa 56 (PMID: 10542133, PMID: 10601738). Gene expression profiling across human tissues shows that IMPG1 mRNA levels are at their highest in retinal tissues (PMID: 30239781). Within the eye, IMPG1 expression is detected in cone and rod photoreceptor cells, specifically in the outer nuclear layer (PMID: 10601738). IMPG1-blocking antibody treatment has been shown to disrupt the differentiation of retinal organoids, indicating a role for IMPG1 in the development of photoreceptors, inner and outer segments, connecting cilia, and the interphotoreceptor matrix (PMID: 29777959). Mouse models of homozygous Impg1 loss-of-function have shown minimal abnormalities limited to the interphotoreceptor matrix during the first 8 months of life (PMID: 32265257), but exhibit late-developing phenotypes between 9 and 14 months of age, such as hyperpigmented subretinal deposits, nummular pigmentation of the fundus, attenuated ERG response, reduced retinal thickness in the outer layer, photoreceptor cell loss, and disorganization of the interphotoreceptor matrix (PMID: 36140676).

In summary, IMPG1 is definitively associated with IMPG1-related recessive retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on September 7th, 2023 (SOP Version 9).